Novel chelating agents, based on cis,cis-1,3,5-triaminocyclohexane (tach) as a platform for introducing a wide variety of metal binding functional groups, continue to be explored for both radio- and chemotherapeutic applications. Numerous novel chelating agents based upon tach have been synthesized, characterized, and evaluated for forming metal complexes with a variety of transition metal ions. Specifically, tris(pyridyl)triamine derivatives of tach (tachpyr) continue to be investigated for chemotherapeutic applications. These ligands disrupt cellular iron transport and storage mechanisms activating a pathway for apoptotic cytotoxicity. Studies with Fe(II)[tachpyr] have also demonstrated the reactive oxidative nature of the ligand with Fe(III) forming Fe(II) and then cycling through redox cycles and Fenton chemistry. Preliminary structure activity relationship (SAR) studies into tuning lipophilicy and electronic nature of the pyridine donors of tachpyr have indicated that the introduction of methyl substituents onto the aromatic rings of TACHpyr inpact the fundamental structure and stability of the metal complexes formed. Preliminary SAR information indicates severe limitations of the 6-position of the pyridyl ring, but also enhancement of activity with substitution at the 3-position due to this providing a driving force for oxidative elimination of the ligand concurrent with metal complexation. Further studies to introduce electron-withdrawing groups to perturb the electronic nature of the environment of the chelated Fe metal ion as well as to alter the overall charge of the complex are ongoing. In parallel, modifications are also being planned to increase the biological half-life of these agents. This study has since been expanded to include a less geometrically constrained triamine, tren, and all of the previously evaluated compounds based on tach have been or are being synthesized for a parallel evaluation. Two different bifunctional tachpyr derivatives have been prepared. Their conjugation chemistry has been established as well as a novel colorometic assay for determining the number of tachpyr and other ligands conjugated to protein. Current plans include in vitro cell targeting and toxicity studied with a Herceptin conjugate followed by translation to animal based model systems.Copper complexes of several TACH ligands that demonstrated the ability to hydrolytically cleave DNA phosphate ester bonds in model compounds, to cleave plasmid DNA, and to exert significant cytotoxicity in vitro continue to be investigated. This project has recently been reactivated and these studies are now being re-evaluated prior to being carried forward again into murine tumor model systems.The entire library of TACHpyr chelating agents has also been evaluated for their utility as anti-angiogenesis agents based upon that Cu(II) is a co-factor of angiogenesis and that depletion of Cu(II) has been shown to have marked effects on tumor growth and vasculature development. We have identified several substantial lead compounds and are in the process of both screening additional compounds and re-evaluating the lead compounds on a larger scale before proceeding to animal model systems.